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Nano-theranostics for parkinson's disease

Active Publication Date: 2020-08-13
IOWA STATE UNIV RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text talks about using nanoparticles to enhance the effectiveness of Abs or fragments used as therapy. This is because nanoparticles can help protect the Abs or fragments from degrading or being taken into the wrong organ. Additionally, nanoparticles can even help the Abs or fragments pass across the blood brain barrier. This is good news because it means that the therapy can be more effective and targeted to the desired area.

Problems solved by technology

This makes them a poor target for development of novel management strategies, including diagnostics and therapeutics to stop, slow, or reverse PD.
By sharing the same epitopes as monomeric αSyn, binding molecules, such as antibodies, which recognize both are not useful as a diagnostic because they would detect both forms of αSyn and give false positive results.
The binding molecules would also not be useful as a treatment for LB containing diseases because they would bind to and interrupt the normal function of αSyn and be detrimental to the patient.
Thus, there are no antibodies suitable to be used for either a detection assay or as a therapeutic as the cross reactivity to both forms would assay for the physiological αSyn as well as the aggregates and prevent the normal function of αSyn in a subject if used as a therapeutic.
Due to this limitation, there is not currently an assay for early accurate diagnosis of PD, nor are there efficacious drugs to prevent, slow progression, or reverse disease.

Method used

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  • Nano-theranostics for parkinson's disease
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  • Nano-theranostics for parkinson's disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0211]In order to generate antibodies specific to the toxic aggregates of human αSyn, both polyclonal and monoclonal antibodies were generated. The polyclonal antibodies were generated by first aggregating native human αSyn in vitro and then using the aggregates to immunize mice. The mice were injected with a primary injection followed by three booster doses admixed with an alum adjuvant. Mouse sera was then selectively enriched for the HA-PAbs through the depletion of antibodies which bound to targets other than the aggregated human αSyn. The monoclonal antibodies were generated using murine hybridomas created by the fusion of murine splenic plasma cells with myeloma cells.

[0212]The HA-PAbs were screen by exposing them to epitopes unique to native αSyn, epitopes common to αSyn and βSyn, and epitopes shared between native αSyn and toxic αSyn. As shown by the different intensities in FIG. 1, the toxic aggregated αSyn has unique epitopes that are absent in the physiological monomeric ...

example 2

[0215]To show that the HM-PAbs of Example 1 can discriminate between subjects with Parkinson's disease (PD) and subjects which were age matched (AM) an immunoblot comparison was carried out. Serum and cerebral spinal fluid (CSF) samples were taken from both PD patients and AM subjects. The protein was then extracted from all the samples and using an immunoblot with HM-PAbs as the primary antibody, it was shown that the antibodies could detect the aggregate form in both the CSF and sera of the subjects (see FIG. 3).

[0216]Additionally, the HM-PAbs showed that PD patients contained a higher amount of aggregate αSyn in their CSF for every comparison with AM subjects (see FIG. 3). This discriminatory ability of the HM-PAbs may be used as an early detection test for aiding in the diagnostic of subjects for αSyn aggregate diseases, such as PD, LB dementia, and other synucleoinopathies.

[0217]Therefore, it is possible to specifically detect aggregate αSyn in both the CSF and sera of subjects...

example 3

[0218]The aggregate specific HM-MAbs of Example 1 also show an ability to discriminate between patients with PD and AM subjects. Sera samples were taken from patients with PD and AM subjects and the protein isolated in order to determine if the HM-MAbs could detect aggregate αSyn in a subject's sample. As shown in FIG. 4, the HM-MAbs were able to detect aggregate αSyn in the sera of both patients with PD and AM subjects.

[0219]To show that the HM-MAbs have diagnostics ability, an indirect, competitive semi-quantitative Enzyme Immuno Assay (EIA) was developed. To first show the ability of the EIA to distinguish between aggregate and monomeric forms of αSyn, aggregate EIA was immobilized to the EIA plate and then either the monomer or aggregate αSyn was added as a free analyte to compete for the primary antibody. The IgM HM-MAbs from hybridoma strain 3A8 was then added to each well and allowed to bind with the immobilized aggregate αSyn or to the free analyte. The EIA plate was then wa...

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Abstract

Provided are aggregate alpha-synuclein specific antibodies as well as fragments, derivatives, and variants thereof as well as method related thereto for the early diagnostic and treatment of Parkinson's Disease and other Lewy body- and Lewy neurite-based diseases. Assays, kits, systems, and nanoparticle encapsulated compositions related to the antibodies or fragments, derivatives, and variants thereof are also disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority under 35 U.S.C. § 119 to provisional application Ser. No. 62 / 804,805, filed Feb. 13, 2019, herein incorporated by reference in its entirety.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Feb. 11, 2020, is named 2020-02-13_P12741US01_04793_Narasimhan_seq_ST25.txt and is 13,745 bytes in size.FIELD OF THE INVENTION[0003]The present invention relates to an early screening test for Parkinson's Disease and other Lewy body- and Lewy neurite-based diseases and related diseases and further used in treatment of such related diseases. The present invention also relates to binding molecules, and methods of producing such binding molecules, that preferentially bind aggregated alpha-synuclein without binding monomer alpha-synuclein.BACKGROUND OF THE INVENTIO...

Claims

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Application Information

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IPC IPC(8): C07K16/18G01N33/68G01N33/58
CPCG01N2800/2821C07K2317/92G01N33/587C07K2317/565G01N33/582G01N33/6896C07K2317/33G01N33/581C07K16/18G01N2800/2835C07K2317/24C07K2317/622C07K2317/56
Inventor NARASIMHAN, BALAJIMALLAPRAGADA, SURYAKANTHASAMY, ANUMANTHA G.JOHN, MANOHARANANTHARAM, VELLAREDDY
Owner IOWA STATE UNIV RES FOUND
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